The developing cerebral cortex is a sensitive target for genetic diseases and for gestational exposure to toxins, infection and radiation. Despite this, the basic cellular and molecular mechanisms of cortical development, particularly early cortical development are not well understood. Using a novel 3D cortical hemisphere explant approach and reporter mice, we will examine the cellular behaviors that initiate cortical plate formation and determine how the secreted ligand, Reelin coordinates these behaviors. We will focus on the role of Reelin-dependent modulation of the focal adhesion adaptor protein Paxillin that we find dynamically expressed during early cortical development and aberrantly expressed in reeler mice cortices that lack Reelin. We are using pharmacological and RNAi-based approaches to target downstream signaling elements in the Reelin signaling pathway to determine Reelin's and Paxillin's role(s) in triggering and/or sustaining this morphological differentiation and motility. These studies will help resolve competing models of Reelin function, while providing further molecular and cellular insights into the formation of a cellular layer of the cerebral cortex. Insight into Reelin's role in cortical development will provide a general insight into the development and organization of neurons throughout the central nervous system. In adults, Reelin is up regulated in epileptic foci, and in response to nerve injury. Reelin may therefore have additional important roles in healing and functional recovery. PUBLIC HEALTH RELEVANCE: Brain malformations are increasingly appreciated as an underlying cause of certain forms of epilepsy, mental retardation, autism, dyslexia and reading disorders. This proposal examines molecular and cellular events that occur at an early stage of brain development, but that have a major impact on later brain function and cognition. The work will provide a framework for understanding the etiology of cerebral cortical malformations.